The value of neck adipose tissue as a predictor for metabolic risk in health and type 2 diabetes.

Upper-body adiposity is adversely associated with metabolic health whereas the opposite is observed for the lower-body. The neck is a unique upper-body fat depot in adult humans, housing thermogenic brown adipose tissue (BAT), which is increasingly recognised to influence whole-body metabolic health. Loss of BAT, concurrent with replacement by white adipose tissue (WAT), may contribute to metabolic disease, and specific accumulation of neck fat is seen in certain conditions accompanied by adverse metabolic consequences. Yet, few studies have investigated the relationships between neck fat mass (NFM) and cardiometabolic risk, and the influence of sex and metabolic status. Typically, neck circumference (NC) is used as a proxy for neck fat, without considering other determinants of NC, including variability in neck lean mass. In this study we develop and validate novel methods to quantify NFM using dual x-ray absorptiometry (DEXA) imaging, and subsequently investigate the associations of NFM with metabolic biomarkers across approximately 7000 subjects from the Oxford BioBank. NFM correlated with systemic insulin resistance (Homeostatic Model Assessment for Insulin Resistance; HOMA-IR), low-grade inflammation (plasma high-sensitivity C-Reactive Protein; hsCRP), and metabolic markers of adipose tissue function (plasma triglycerides and non-esterified fatty acids; NEFA). NFM was higher in men than women, higher in type 2 diabetes mellitus compared with non-diabetes, after adjustment for total body fat, and also associated with overall cardiovascular disease risk (calculated QRISK3 score). This study describes the development of methods for accurate determination of NFM at scale and suggests a specific relationship between NFM and adverse metabolic health.

Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity.

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.

OBJECTIVE: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold-induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans. METHODS: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2 ). BAT volume, 18 F-fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography-computerized tomography scan after cold exposure. RESULTS: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = -37.12 ± 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: ß = 0.456; R2 = 0.307; p = 0.001), but not with 18 F-fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity. CONCLUSIONS: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold-induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21.

Adults with metabolically healthy overweight or obesity present more brown adipose tissue and higher thermogenesis than their metabolically unhealthy counterparts.

BACKGROUND: There is a subset of individuals with overweight/obesity characterized by a lower risk of cardiometabolic complications, the so-called metabolically healthy overweight/obesity (MHOO) phenotype. Despite the relatively higher levels of subcutaneous adipose tissue and lower visceral adipose tissue observed in individuals with MHOO than individuals with metabolically unhealthy overweight/obesity (MUOO), little is known about the differences in brown adipose tissue (BAT). METHODS: This study included 53 young adults (28 women) with a body mass index (BMI) ≥25 kg/m2 which were classified as MHOO (n = 34) or MUOO (n = 19). BAT was assessed through a static 18F-FDG positron emission tomography/computed tomography scan after a 2-h personalized cooling protocol. Energy expenditure, skin temperature, and thermal perception were assessed during a standardized mixed meal test (3.5 h) and a 1-h personalized cold exposure. Body composition was assessed by dual-energy x-ray absorptiometry, energy intake was determined during an ad libitum meal test and dietary recalls, and physical activity levels were determined by a wrist-worn accelerometer. FINDINGS: Participants with MHOO presented higher BAT volume (+124%, P = 0.008), SUVmean (+63%, P = 0.001), and SUVpeak (+133%, P = 0.003) than MUOO, despite having similar BAT mean radiodensity (P = 0.354). In addition, individuals with MHOO exhibited marginally higher meal-induced thermogenesis (P = 0.096) and cold-induced thermogenesis (+158%, P = 0.050). Moreover, MHOO participants showed higher supraclavicular skin temperature than MUOO during the first hour of the postprandial period and during the cold exposure, while no statistically significant differences were observed in other skin temperature parameters. We observed no statistically significant differences between MHOO and MUOO in thermal perception, body composition, outdoor ambient temperature exposure, resting metabolic rate, energy intake, or physical activity levels. INTERPRETATION: Adults with MHOO present higher BAT volume and activity than MUOO. The higher meal- and cold-induced thermogenesis and cold-induced supraclavicular skin temperature are compatible with a higher BAT activity. Overall, these results suggest that BAT presence and activity might be linked to a healthier phenotype in young adults with overweight or obesity. FUNDING: See acknowledgments section.

Brown adipose tissue evaluation using water and triglyceride as indices by diffuse reflectance spectroscopy.

Brown adipose tissue (BAT) is related to lipid and glucose metabolism, and BAT evaluation is expected to contribute to disease prevention and treatment. We aimed to establish a BAT evaluation method using simple and non-invasive diffuse reflectance spectroscopy (DRS). We acquired diffuse reflectance spectra of BAT using DRS from rats with cold stimulation and analyzed the second-derivative spectra. To predict the amount of triglyceride in BAT from the second-derivative spectra, partial least-squares regression analysis was performed, and we examined whether BAT weight can be predicted from the amount of triglyceride by single regression analysis. By focusing on changes in the amount of triglyceride in BAT with cold stimulation, it was suggested that this amount could be predicted spectroscopically, and the predicted amount of triglyceride could be used to estimate the BAT weight with cold stimulation. If these results can be translated into humans, they may contribute to preventing metabolic disorders.

Incidence and Risk Factors for Brown Adipose Tissue Uptake in PET Imaging in Pediatric Patients.

BACKGROUND: Positron emission tomography (PET) scans are used in disease diagnosis and evaluation for pediatric oncology patients. Brown adipose tissue (BAT) 18 F-fluorodeoxyglucose-PET uptake is reported in 35% to 47% of pediatric patients. Several risk factors may be associated with BAT uptake. OBJECTIVE: The aim was to determine the incidence and risk factors for BAT in pediatric patients using a consensus-based system and a novel grading scale. METHODS: A total of 285 PET scans in 154 patients were retrospectively reviewed for the presence of BAT from September 2015 through December 2016. A consensus review was done by 2 radiologists, who graded BAT on a 0 to 3 scale and assessed its impact on PET interpretation. RESULTS: The presence of moderate to severe BAT occurred in 11% of PET scans, and 6% of PETs had limited interpretation. Hodgkin lymphoma (n=53) patients had a 3.62-fold increased odds of moderate or severe BAT and a 6.59-fold increased odds of limited interpretation on PET imaging. CONCLUSION: The incidence of BAT was low but impacted radiologic interpretation when present. Further studies with a larger group of Hodgkin lymphoma patients are needed to explore the risk factors associated with moderate or severe BAT.

Automatic segmentation of the interscapular brown adipose tissue in rats based on deep learning using the dynamic magnetic resonance fat fraction images.

OBJECTIVE: The study aims to propose an accurate labelling method of interscapular BAT (iBAT) in rats using dynamic MR fat fraction (FF) images with noradrenaline (NE) stimulation and then develop an automatic iBAT segmentation method using a U-Net model. MATERIALS AND METHODS: Thirty-four rats fed different diets or housed at different temperatures underwent successive MR scans before and after NE injection. The iBAT were labelled automatically by identifying the regions with obvious FF change in response to the NE stimulation. Further, these FF images along with the recognized iBAT mask images were used to develop a deep learning network to accomplish the robust segmentation of iBAT in various rat models, even without NE stimulation. The trained model was then validated in rats fed with high-fat diet (HFD) in comparison with normal diet (ND). RESULT: A total of 6510 FF images were collected using a clinical 3.0 T MR scanner. The dice similarity coefficient (DSC) between the automatic and manual labelled results was 0.895 ± 0.022. For the network training, the DSC, precision rate, and recall rate were found to be 0.897 ± 0.061, 0.901 ± 0.068 and 0.899 ± 0.086, respectively. The volumes and FF values of iBAT in HFD rats were higher than ND rats, while the FF decrease was larger in ND rats after NE injection. CONCLUSION: An automatic iBAT segmentation method for rats was successfully developed using the dynamic labelled FF images of activated BAT and deep learning network.

Tracers and Imaging of Fatty Acid and Energy Metabolism of Human Adipose Tissues.

White adipose tissue and brown adipose tissue (WAT and BAT) regulate fatty acid metabolism and control lipid fluxes to other organs. Dysfunction of these key metabolic processes contributes to organ insulin resistance and inflammation leading to chronic diseases such as type 2 diabetes, metabolic dysfunction-associated steatohepatitis, and cardiovascular diseases. Metabolic tracers combined with molecular imaging methods are powerful tools for the investigation of these pathogenic mechanisms. Herein, I review some of the positron emission tomography and magnetic resonance imaging methods combined with stable isotopic metabolic tracers to investigate fatty acid and energy metabolism, focusing on human WAT and BAT metabolism. I will discuss the complementary strengths offered by these methods for human investigations and current gaps in the field.

Prevention of activated brown adipose tissue on 18F-FDG-PET scans of young lymphoma patients: results of an ancillary study within the EuroNet-PHL-C2 trial.

Activated brown fat (aBAT) is known to affect the evaluation of 18F-FDG PET scans, especially in young patients. The aim of this study was to determine factors influencing the occurrence of aBAT, and to investigate the effectiveness of the two preventive measures, warming and beta-blocker (propranolol) administration. Five-hundred-twenty-eight 18F-FDG-PET scans of 241 EuroNet-PHL-C2 trial patients from 41 nuclear medicine departments in Germany and Czech Republic were screened for aBAT. The occurrence of aBAT was analyzed with patient characteristics (age, sex, body mass index, predisposition to aBAT), weather data at the day of 18F-FDG PET scanning as well as the preventive measures taken. Potentially important factors from univariate analyses were included into a logistic regression model. Warming as a preventive measure was used in 243 18F-FDG-PET scans, propranolol was administered in 36, warming and propranolol were combined in 84, and no preventive measures were taken in 165 scans. Whereas age, sex and body mass index had no clear impact, there was an individual predisposition to aBAT. Logistic regression model revealed that the frequency of aBAT mainly depends on the outside temperature (p = 0.005) and can be effectively reduced by warming (p = 0.004), the administration of unselective beta-blocker or the combination of both. Warming is a simple, cheap and non-invasive method to reduce the frequency of aBAT. However, the effect of warming decreases with increasing outside temperatures. Administration of propranolol seems to be equally effective and provides advantages whenever the positive effect of warming is compromised. The combination of both preventive measures could have an additive effect.

18F-FDG PET/CT technology for the assessment of brown adipose tissue: an updated review.

INTRODUCTION: This review provides an update of 18 F-fluorodeoxyglucose ([18F] FDG) for Brown adipose tissue (BAT) activity quantification, whose role is not completely understood. AREAS COVERED: We conducted an unstructured search of the literature for any studies employing the [18F] FDG PET in BAT assessment. We explored BAT quantification both in healthy individuals and in different pathologies, after cold exposure and as a metabolic biomarker. The assessment of possible BAT modulators by using [18F] FDG PET is shown. Further PET tracers and novel developments for BAT assessments are also described. EXPERT OPINION: Further PET tracers and imaging modalities are under investigation, but the [18F] FDG PET is currently the method of choice for the evaluation of BAT and further multicentric trials are needed for a better understanding of the BAT physiopathology, also after cold stimuli. The modulation of BAT activity, assessed by [18F] FDG PET imaging, seems a promising tool for the management of conditions such as obesity and type 2 diabetes. Moreover, an interesting possible correlation of BAT activation with prognostic [18F] FDG PET indices in cancer patients should be assessed with further multicentric trials.

Repeatability of brown adipose tissue activation measured by [18F]FDG PET after beta3-adrenergic stimuli in a mouse model.

This study aimed to evaluate the repeatability of brown adipose tissue (BAT) activation measured by [18F]FDG-PET after beta3-adrenergic stimuli with CL316243 in mice. METHODS: Male C57BL/6 mice underwent [18F]FDG-PET at baseline without stimulation (T0-NS), on three consecutive days after intravenous administration of the selective ß3-adrenergic agonist CL316243 (T1-CL, T2-CL, T3-CL), and without stimuli after 1 and 2 weeks (T7-NS and T14-NS). The standardized uptake value (SUVmax), BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were measured in each scanning session, with statistical groupwise comparisons by ANOVA and post hoc Tukey test. RESULTS: SUVmax, BMV, and TBG values showed no significant differences between the three PET scans without stimuli, but were significantly higher after CL316243 administration (p < 0.0001). The mean coefficient of variation (CoV) of PET within individuals was 49 % at baseline but only 9 % with pharmacological stimulation. CONCLUSIONS: The study demonstrated that administration of the selective ß3-adrenergic receptor agonist CL316243 (CL) in mice leads to consistent metabolic activation of brown adipose tissue (BAT), as measured by [18F]FDG-PET. We also demonstrated metabolic activation by repeated pharmacological challenge, without evidence of hysteresis. Thus, the methods used in the current work should serve for further studies on BAT metabolism in experimental animals, with translational value for clinical research.

Human brown adipose tissue function: insights from current in vivo techniques.

The identification of brown adipose tissue (BAT) as a thermogenic organ in human adults approximately 20 years ago raised the exciting possibility of activating this tissue as a new treatment for obesity and cardiometabolic disease. [18F]Fluoro-2-deoxyglucose (18F-FDG) combined positron emission tomography and computed tomography (PET/CT) scanning is the most commonly used imaging modality to detect and quantify human BAT activity in vivo. This technique exploits the substantial glucose uptake by BAT during thermogenesis as a marker for BAT metabolism. 18F-FDG PET has provided substantial insights into human BAT physiology, including its regulatory pathways and the effect of obesity and cardiometabolic disease on BAT function. The use of alternative PET tracers and the development of novel techniques such as magnetic resonance imaging, supraclavicular skin temperature measurements, contrast-enhanced ultrasound, near-infrared spectroscopy and microdialysis have all added complementary information to improve our understanding of human BAT. However, many questions surrounding BAT physiology remain unanswered, highlighting the need for further research and novel approaches to investigate this tissue. This review critically discusses current techniques to assess human BAT function in vivo, the insights gained from these modalities and their limitations. We also discuss other promising techniques in development that will help dissect the pathways regulating human thermogenesis and determine the therapeutic potential of BAT activation.

Triglyceride-Rich Lipoprotein-Mediated Polymer Dots for Multimodal Imaging Interscapular Brown Adipose Tissue Capillaries.

Brown adipose tissues (BATs) have been identified as a promising target of metabolism disorders. [18F]FDG-PET (FDG = fluorodeoxyglucose; PET = positron emission tomography) has been predominantly employed for BAT imaging, but its limitations drive the urgent need for novel functional probes combined with multimodal imaging approaches. It has been reported that polymer dots (Pdots) display rapid BAT imaging without additional cold stimulation. However, the mechanism by which Pdots image BAT remains unclear. Here, we made an intensive study of the imaging mechanism and found that Pdots can bind to triglyceride-rich lipoproteins (TRLs). By virtue of their high affinity to TRLs, Pdots selectively accumulate in capillary endothelial cells (ECs) in interscapular brown adipose tissues (iBATs). Compared to poly(styrene-co-maleic anhydride)cumene terminated (PSMAC)-Pdots with a short half-life and polyethylene glycol (PEG)-Pdots with low lipophilicity, naked-Pdots have good lipophilicity, with a half-life of about 30 min and up to 94% uptake in capillary ECs within 5 min, increasing rapidly after acute cold stimulation. These results suggested that the accumulation changes of Pdots in iBAT can reflect iBAT activity sensitively. Based on this mechanism, we further developed a strategy to detect iBAT activity and quantify the TRL uptake in vivo using multimodal Pdots.

Human thermogenic adipose tissue.

Human thermogenic adipose tissue has long been touted as a promising therapeutic target for obesity and its associated metabolic diseases. Here, we provide a brief overview of the current knowledge of in vivo human thermogenic adipose tissue metabolism. We explore the evidence provided by retrospective and prospective studies describing the association of brown adipose tissue (BAT) [18F]fluorodeoxyglucose accumulation and various cardiometabolic risk factors. Although these studies have been invaluable in generating hypothesis, it has also raised some questions about the reliability of this method as an indicator of BAT thermogenic capacity. We discuss the evidence in support of human BAT functioning as a local thermogenic organ and energy sink, as an endocrine organ, and as a biomarker of adipose tissue health.

[18F]FDG and [11C]PK11195 PET imaging in the evaluation of brown adipose tissue - effects of cold and pharmacological stimuli and their association with crotamine intake in a male mouse model.

This study aimed to evaluate the role of positron emission tomography (PET) with [11C]PK11195 and [18F]FDG in the characterization of brown adipose tissue (BAT). METHODS: Male C57BL/6 mice were studied with the glucose analogue [18F]FDG (n = 21) and the TSPO mitochondrial tracer [11C]PK11195 (n = 28), without stimulus and after cold (6-9 °C) or beta-agonist (CL316243) stimuli. PET studies were performed at baseline and after 21 days of daily treatment with crotamine, which is a peptide described to induce adipocyte tissue browning and to increase BAT metabolism. Tracer uptake (SUVmax) was measured in the interscapular BAT and translocator protein 18 kDa (TSPO) expression was evaluated by immunohistochemistry. RESULTS: The cold stimulus increased [18F]FDG uptake compared to no-stimulus (5.21 ± 1.05 vs. 2.03 ± 0.21, p < 0.0001) and to beta-agonist stimulus (2.65 ± 0.39, p = 0.0003). After 21 days of treatment with crotamine, there was no significant difference in the [18F]FDG uptake compared to the baseline in the no-stimulus group and in the cold-stimulus group, with a significant increase in uptake after CL stimulus (baseline: 2.65 ± 0.39; 21 days crotamine: 4.77 ± 0.81, p = 0.0003). Evaluation of [11C]PK11195 at baseline shows that CL stimulus increases the BAT uptake compared to no-stimulus (4.47 ± 0.66 vs. 3.36 ± 0.68, p = 0.014). After 21 days of treatment with crotamine, there was no significant difference in the [11C]PK11195 uptake compared to the baseline in the no-stimulus group (2.94 ± 0.58, p = 0.7864) and also after CL stimulus (3.55 ± 0.79, p = 0.085). TSPO expression correlated with [11C]PK11195 uptake (r = 0.83, p = 0.018) but not with [18F]FDG uptake (r = 0.40, p = 0.516). CONCLUSIONS: [11C]PK11195 allowed the identification of BAT under thermoneutral conditions or after beta3-adrenergic stimulation in a direct correlation with TSPO expression. The beta-adrenergic stimulus, despite presenting a lower intensity of glycolytic activation compared to cold at baseline, allowed the observation of an increase in BAT uptake of [18F]FDG after 21 days of crotamine administration. Although some limitations were observed for the metabolic changes induced by crotamine, this study reinforced the potential of using [11C]PK11195 and/or [18F]FDG-PET to monitor the activation of BAT.

Image registration and mutual thresholding enable low interimage variability across dynamic MRI measurements of supraclavicular brown adipose tissue during mild cold exposure.

PURPOSE: Activated brown adipose tissue (BAT) enhances lipid catabolism and improves cardiometabolic health. Quantitative MRI of the fat fraction (FF) of supraclavicular BAT (scBAT) is a promising noninvasive measure to assess BAT activity but suffers from high scan variability. We aimed to test the effects of coregistration and mutual thresholding on the scan variability in a fast (1 min) time-resolution MRI protocol for assessing scBAT FF changes during cold exposure. METHODS: Ten volunteers (age 24.8 ± 3.0 years; body mass index 21.2 ± 2.1 kg/m2 ) were scanned during thermoneutrality (32°C; 10 min) and mild cold exposure (18°C; 60 min) using a 12-point gradient-echo sequence (70 consecutive scans with breath-holds, 1.03 min per dynamic). Dynamics were coregistered to the first thermoneutral scan, which enabled drawing of single regions of interest in the scBAT depot. Voxel-wise FF changes were calculated at each time point and averaged across regions of interest. We applied mutual FF thresholding, in which voxels were included if their FF was greater than 30% FF in the reference scan and the registered dynamic. The efficacy of the coregistration was determined by using a moving average and comparing the mean squared error of residuals between registered and nonregistered data. Registered scBAT ΔFF was compared with single-scan thresholding using the moving average method. RESULTS: Registered scBAT ΔFF had lower mean square error values than nonregistered data (0.07 ± 0.05% vs. 0.16 ± 0.14%; p < 0.05), and mutual thresholding reduced the scBAT ΔFF variability by 30%. CONCLUSION: We demonstrate that coregistration and mutual thresholding improve stability of the data 2-fold, enabling assessment of small changes in FF following cold exposure.

Imaging Brown Adipose Tissue with TSPO PET Tracers in Preclinical Animal Studies.

Brown adipose tissue (BAT) is closely associated with thermogenesis and related to numerous diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and obesity. Using molecular imaging technologies to monitor BAT could facilitate etiology elucidation, disease diagnosis, and therapeutics development. Translocator protein (TSPO), an 18 kDa protein that mainly locates on the outer mitochondrial membrane, has been proven as a promising biomarker for monitoring BAT mass. Here, we lay out the steps for imaging BAT with TSPO PET tracer [18F]-DPA in mouse studies.

Assessment of Brown and Beige Adipose Tissue Activation in Mice Using PET/CT Imaging.

In response to cold induction, brown adipose tissues (BAT) and emerged brown-like adipocytes (beige adipocytes) in subcutaneous white adipose tissues (WAT browning/beiging) are activated. Thermogenesis is increased during glucose and fatty acid uptake and metabolism in adult humans and mice. This activation of BAT or WAT beiging to generate heat helps to counteract diet-induced obesity. This protocol applies the glucose analog radiotracer 18F-fluorodeoxyglucose (FDG), coupled with positron emission tomography and computed tomography (PET/CT) scanning to evaluate cold-induced thermogenesis in the active BAT (interscapular region) and browned/beiged WAT (subcutaneous adipose region) in mice. The PET/CT scanning technique not only can quantify cold-induced glucose uptake in well-known BAT and beige-fat depots but also helps to visualize the anatomical location of novel uncharacterized mouse BAT and beige fat where cold-induced glucose uptake is high. Histological analysis is further employed to validate signals of delineated anatomical regions in PET/CT images as bona fide mouse BAT or beiged WAT fat depots.

Development and validation of a nonenhanced CT based radiomics model to detect brown adipose tissue.

Purpose: It has been reported that brown adipose tissue (BAT) has a protective effect regarding cardiovascular disease. Positron emission tomography-computed tomography (PET-CT) is the reference method for detecting active BAT; however, it is not feasible to screen for BAT due to the required radionuclides and high-cost. The purpose of this study is to develop and validate a nonenhanced CT based radiomics model to detect BAT and to explore the relationship between CT radiomics derived BAT and cardiovascular calcification. Patients and methods: 146 patients undergoing 18F-FDG PET-CT were retrospectively included from two centers for model development (n = 86) and external validation (n = 60). The data for the model development were randomly divided into a training cohort and an internal validation cohort with a 7:3 ratio, while the external validation data were divided 1:1 into a propensity score matching (PSM) cohort and a randomly sex matched cohort. Radiomics features of BAT and non-BAT depots were extracted from regions of interest (ROI) on nonenhanced CT corresponding to PET studies. Inter-class correlation coefficient (ICC) and Pearson's correlation analysis were performed to select radiomics features with high consistency. Next, least absolute shrinkage and selection operator (LASSO) with linear regression model was used to select radiomics features for model construction. Support vector machine (SVM) was used to develop the model and a radiomics score (RS) was calculated for each depot. The diagnostic performance of the radiomics model was evaluated both on a per-depot and per-patient basis by calculating the area under the receiver operating characteristic curve (AUROC). We further divided patients into BAT-RS group and non-BAT-RS group based on radiomics score and compared their cardiovascular calcification by calculating calcium volume and score. Results: A total of 22 radiomics features were selected for model construction. On a per-depot basis, the AUROCs were 0.87 (95% CI: 0.83-0.9), 0.85 (95% CI: 0.79-0.90), 0.72 (95% CI: 0.67-0.77) and 0.74 (95% CI: 0.69-0.79) for detecting BAT in the training, internal validation, external validation 1 and external validation 2 cohorts, respectively. On a per-patient basis, the radiomics model had high AUROCs of 0.91 (95% CI: 0.84-0.98), 0.77 (95% CI: 0.61-0.92) and 0.85 (95% CI: 0.72-0.98) in the training, external validation 1 and external validation 2 cohorts, respectively. When grouping based on the radiomics model, the BAT-RS group had lower odds of coronary artery calcium (CAC) and thoracic aorta calcium (TAC) compared with the non-BAT-RS group (CAC: 2.8% vs. 20.3%, p = 0.001; TAC: 19.4% vs. 39.2%, p = 0.009). The BAT-RS group had less CAC volume (4.1 ± 4.0 mm3 vs. 147.4 ± 274.3 mm3; p = 0.001), CAC score (2.8 ± 3.0 vs. 169.1 ± 311.5; p = 0.001), TAC volume (301.4 ± 450.2 mm3 vs. 635.3 ± 1100.7 mm3; p = 0.007) and TAC score (496.2 ± 132.6 vs. 749.2 ± 1297.3; p = 0.007) than the non-BAT-RS group. Conclusion: We developed and validated a nonenhanced CT based reliable radiomics model for detecting BAT with PET-CT findings as reference standard. Radiomics signatures from nonenhanced CT can reliably detect BAT and have promising potential to be used in routine clinical settings. Importantly, our study showed that patients with BAT had less cardiovascular calcification.